Project Summary/Abstract Malaria is a leading cause of human death and illness, causing over 200 million cases of clinical malaria and 400,000 deaths each year. Traditional measures to control and cure malaria are becoming increasingly less effective and there is an urgent need for the development of new drugs and vaccines. A strategic hurdle for development of new anti-malarial therapeutics remains the lack of experimentally validated functional information about most Plasmodium falciparum genes. This is a critical gap of knowledge hindering identification of new drugs and vaccines. Therefore, efficient development of these new therapies requires a better understanding of essential metabolic pathways and weaknesses in the parasite?s physiology to target. Our approach is to use functional genomics studies to identify essential genes of P. falciparum through whole genome saturation-level piggyBac mutagenesis and forward genetic screens. Preliminary studies have validated this approach to identify essential and dispensable processes for asexual blood-stage growth under ideal in vitro culture conditions. We will extend these studies to identify factors essential for in vivo survival, too. Through this project, we expect to identify most genes critical for parasite blood-stage growth and development helping to identify and prioritize novel targets on which drug and vaccine discovery projects can be initiated. In addition, this project will provide the malaria research community with a large collection of gene knockouts valuable for many other research projects.